WO2002087546A2 - Method for manufacturing a low dose pharmaceutical composition - Google Patents

Method for manufacturing a low dose pharmaceutical composition Download PDF

Info

Publication number
WO2002087546A2
WO2002087546A2 PCT/IB2002/000766 IB0200766W WO02087546A2 WO 2002087546 A2 WO2002087546 A2 WO 2002087546A2 IB 0200766 W IB0200766 W IB 0200766W WO 02087546 A2 WO02087546 A2 WO 02087546A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
active ingredient
pharmaceutical composition
silicon dioxide
pharmaceutically acceptable
Prior art date
Application number
PCT/IB2002/000766
Other languages
English (en)
French (fr)
Other versions
WO2002087546A3 (en
Inventor
Daniel Scott Gierer
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EEP200300537A priority Critical patent/EE200300537A/xx
Priority to MXPA03009391A priority patent/MXPA03009391A/es
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to AU2002236166A priority patent/AU2002236166B2/en
Priority to EA200301040A priority patent/EA005949B1/ru
Priority to NZ528886A priority patent/NZ528886A/en
Priority to JP2002584892A priority patent/JP2004531537A/ja
Priority to YUP-815/03A priority patent/YU81503A/sh
Priority to IL15839002A priority patent/IL158390A0/xx
Priority to BR0209283-2A priority patent/BR0209283A/pt
Priority to KR1020037014223A priority patent/KR100568380B1/ko
Priority to EP02702671A priority patent/EP1383482B1/en
Priority to DE60221238T priority patent/DE60221238T2/de
Priority to DK02702671T priority patent/DK1383482T3/da
Priority to CA002445519A priority patent/CA2445519C/en
Priority to APAP/P/2003/002900A priority patent/AP2003002900A0/en
Priority to HU0401391A priority patent/HUP0401391A3/hu
Priority to UA2003109816A priority patent/UA75135C2/uk
Priority to SK1355-2003A priority patent/SK286536B6/sk
Publication of WO2002087546A2 publication Critical patent/WO2002087546A2/en
Publication of WO2002087546A3 publication Critical patent/WO2002087546A3/en
Priority to IS6985A priority patent/IS6985A/is
Priority to NO20034709A priority patent/NO20034709L/no
Priority to HR20030858A priority patent/HRP20030858A2/xx
Priority to HK04108533A priority patent/HK1065705A1/xx

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a method for manufacturing a pharmaceutical composition having uniform drug distribution and potency including the compositions and medicaments produced therefrom, in particular, methods and compositions for use in the manufacture of low dosage tablet compositions containing a silicon dioxide to reduce loss of the active ingredient during the manufacturing process.
  • BACKGROUND US 5,552,412 describes a class of potent and orally active selective estrogen receptor modulators (SERMS) (e.g., derivatives of tetrahydronaphthalen-2-ol) which are useful in the treatment or prevention of breast cancer, osteoporosis, obesity, cardiovascular disease, hypercholesterolemia, endometriosis and prostatic disease.
  • SERMS selective estrogen receptor modulators
  • These particular SERMS are of interest due to their improved oral bioavailability over current commercially available SERMS (e.g. raloxifene).
  • the SERMS described in US 5,552,412 are very potent thus allowing for low dosage forms.
  • the formulation of compositions at the lower dose range presents a challenge in maintaining consistent potency and uniformity in the drug product manufacturing process.
  • the present invention provides a method for manufacturing a pharmaceutical composition having uniform drug distribution and potency.
  • the method includes (in the following order) the steps of: (1 ) blending silicon dioxide and at least one pharmaceutically acceptable excipient, carrier or diluent in a high shear granulator for an appropriate amount of time (about 5 minutes) to produce a blended mixture; (2) adding an active ingredient to the granulator and blending for an additional period of time (about 10 to about 15 minutes) to form an active blend; (3) transferring the active blend from the granulator to a blender; (4) optionally, adding one or more additional pharmaceutically acceptable excipients, carriers or diluents to the active blend; and (5) blending for a suitable period of time (about 5 minutes) to form a pharmaceutical composition having uniform distribution of the active ingredient and uniform potency.
  • the resultant blended composition may then be processed further into a desired unit dosage form.
  • the active ingredient is present in an amount from about 0.01 to 10.0 mg per unit dose (preferably from about 0.05 to about 5.0 mg, more preferably from about 0.05 to about 4.0 mg, even more preferably from about 0.1 to about 3.5 mg, and most preferably from about 0.1 to about 2.5 mg per unit dose) and the silicon dioxide is present in an amount from about 0.1 to about 2% by weight of the unit dosage form (more preferably from about 0.15 to about 1.0% by weight of the unit dosage form and most preferably from about 0.25 to about 0.75% by weight of the unit dosage form).
  • a pharmaceutical composition is provided that is prepared using the method described above.
  • a low dosage pharmaceutical composition is provided that comprises an active ingredient (preferably lasofoxifene), a silicon dioxide, and at least one pharmaceutically acceptable excipient, carrier, or diluent wherein the active ingredient is present in an amount less than 4.0% w/w active ingredient (more preferably > about 0.01% w/w active ingredient and ⁇ 4% w/w active ingredient, even more preferably > about 0.01% w/w active ingredient and ⁇ about 3.5% w/w active ingredient, most preferably > about 0.1 % w/w active ingredient and ⁇ about 2.5% w/w active ingredient) and the silicon dioxide is present in an amount from about 0.1 to about 2 weight percent.
  • an active ingredient preferably lasofoxifene
  • a silicon dioxide preferably at least one pharmaceutically acceptable excipient, carrier, or diluent
  • the active ingredient is present in an amount less than 4.0% w/w active ingredient (more preferably > about 0.0
  • a medicament is provided that is prepared by the method described above into a unit dosage form, in particular a low dosage form.
  • uniform distribution refers to a blended mixture which meets the FDA criteria (Guidance for Industry ANDA's: Blend Uniformity Analysis, published August 1999) of 10 individual blend samples achieving 90-110% potency of the theoretical strength with an RSD of ⁇ 5% for all blend samples.
  • uniform potency refers to a blended mixture that maintains a drug substance activity level greater than or equal to about 90% throughout the manufacturing process.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • active ingredient refers to a therapeutically active compound, as well as any prodrugs thereof and pharmaceutically acceptable salts, hydrates and solvates of the compound and the prodrugs.
  • appropriate period of time or “suitable period of time” refers to the period of time necessary to achieve a desired effect or result.
  • a mixture may be blended until a potency distribution is reached that is within an acceptable qualitative range for a given application or use of the blended mixture.
  • unit dose or "unit dosage” refers to a physically discrete unit that contains a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect.
  • the unit dose or unit dosage may be in the form of a tablet, capsule, sachet, etc. referred to herein as a "unit dosage form.”
  • the present invention provides a process for maintaining uniformity and potency during the manufacture of a pharmaceutical composition containing a highly potent active ingredient.
  • the process includes a means for reducing the loss of active ingredients that adhere to the metal surfaces of equipment during the manufacturing process of a pharmaceutical composition or medicament.
  • Active ingredients of particular interest are SERM compounds of Formula (I) below:
  • prodrug thereof or a pharmaceutically acceptable salt, hydrate or solvate of the compound or the prodrug.
  • Preferred compounds include c/ ' s-6-(4-fluoro-phenyl)-5-[4-(2-piperidin- 1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol; (-)-c/s-6-phenyl-5-[4- (2-pyrrolidin-1 -yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol; cis-6- phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2- ol; c/s-1 -[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1 ,2,3,4- tetrahydrohaphthalen-1 -(4'-pyrrolidinoethoxy
  • a more preferred compound is c/s-6-phenyl-5-[4-(2-pyrrolidin-1 - ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol; a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of the compound or the prodrug.
  • the compounds of Formula (I) are very potent compounds thus requiring special handling to reduce operator exposure during the manufacturing process.
  • the compounds of Formula (I) may be sensitive to oxidation which may limit or preclude the use of liquids and materials containing peroxide contaminants (e.g., polyethylene glycols) during drug product manufacture. Conventional methods for manufacturing tablets typically use a wet or dry granulation step prior to compression into a tablet.
  • the types of mixing processes for a dry granulation can be divided into two broad categories: (i) batch, and (ii) continuous.
  • the most prevalent type used in the pharmaceutical industry is the batch type which mixes a sub-lot or total lot of a formulation at one time.
  • particle movement is achieved by rotation of the entire mixer shell or body.
  • a Blend/Mill/Blend dry granulation process the following steps are generally employed:
  • High speed granulators are stationary shell mixers with a large mixer- scraper blade that mixes the ingredients, eliminates dead spots in the mixer container and presents the mixer contents to a high-speed chopper blade which intimately mixes the ingredients.
  • the equipment is extremely rapid and provides intimate solids/solids mixing.
  • rotating mixing impellers mix the particles centrifugally at high speed causing a highly fluidized vortex of material.
  • a chopper rotating at a very high speed, interrupts the ascending circulation of the material and diverts the product into a vertical flow.
  • suitable high-speed granulators include SpectrumTM and Pharma MatrixTM (both available from Niro Pharma Systems, Columbia, MD).
  • the present invention provides a dry process that comprises the following steps: (i) blending at least one pharmaceutically acceptable excipient, carrier or diluent in a high shear granulator for an appropriate amount of time;
  • the final pharmaceutical composition is processed into a unit dosage form (e.g., tablet, capsule or sachet) and then packaged for distribution.
  • a unit dosage form e.g., tablet, capsule or sachet
  • the processing step will vary depending upon the particular unit dosage form. For example, a tablet is generally compressed under pressure into a desired shape and a capsule or sachet employs a simple fill operation. Those skilled in the art are well aware of the procedures used for manufacturing the various unit dosage forms.
  • the active blend generally includes one or more pharmaceutically acceptable excipients, carriers or diluents.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the active ingredient is being applied.
  • a tablet formulation includes materials such as diluents, binders, lubricants, disintegrants and mixtures thereof.
  • Suitable diluents include various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (e.g., sodium chloride), powdered sugar, and powdered cellulose derivatives.
  • a volume mean diameter drug substance particle size of less than or equal to about 30 microns is preferably utilized.
  • Preferred diluents are microcrystalline cellulose (e.g., Avicel® PH102 or PH101 available from FMC Pharmaceutical, Philadelphia, PA) and lactose.
  • the mean particle size for the microcrystalline cellulose generally ranges from about 90 ⁇ m to about 200 ⁇ m.
  • Suitable grades of lactose include anhydrous lactose (about 152 ⁇ m mean), lactose monohydrate and spray dried lactose (e.g., Fast FloTM lactose, about 87 ⁇ m mean, available from Foremost Corp., Baraboo, Wl). If desired, a binder may be added.
  • Suitable binders include substances such as celluloses (e.g., cellulose, methylcellulose, ethylcellulose, and hydroxymethylcellulose), polypropylpyrrolidone, polyvinylprrolidone, gelatin, gum arabic, polyethylene glycol, starch, sugars (e.g., lactose, sucrose, fructose, and glucose), natural and synthetic gums (e.g., acacia, alginates, and gum arabic) and waxes.
  • celluloses e.g., cellulose, methylcellulose, ethylcellulose, and hydroxymethylcellulose
  • polypropylpyrrolidone polyvinylprrolidone
  • gelatin e.g., methylcellulose, ethylcellulose, and hydroxymethylcellulose
  • gum arabic e.g., cellulose, methylcellulose, ethylcellulose, and hydroxymethylcellulose
  • sugars e.g., lactose, sucrose, fruct
  • a lubricant is typically used in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • Suitable lubricants include slippery solids such as talc, magnesium and calcium stearate, stearic acid, light anhydrous silicic acid, and hydrogenated vegetable oils.
  • a preferred lubricant is magnesium stearate.
  • Disintegrants may also be added to the composition to break up the dosage form and release the compound.
  • Suitable disintegrants include starches (e.g., corn or potato starches and hydroxypropylstarch), clays, celluloses (e.g., cellulose, wood cellulose, methyl- or ethyl-cellulose, low substituted hydroxypropylcellulose, and carboxymethylcellulose), agar, algins (e.g., alginic acid), powdered natural sponge, cation-exchange resins, citrus pulp, bentonite, sodium bicarbonate, calcium phosphate, calcium citrate, sodium lauryl sulfate, and gums (e.g., guar gum).
  • starches e.g., corn or potato starches and hydroxypropylstarch
  • clays e.g., cellulose, wood cellulose, methyl- or ethyl-cellulose, low substituted hydroxypropylcellulose, and carboxymethylcellulose
  • algins e.g.,
  • Other useful additives include materials such as agents for retarding dissolution (e.g., paraffin), resorption accelerators (e.g., quaternary ammonium compounds), surface active agents (e.g., cetyl alcohol, glycerol monostearate, and sodium lauryl sulfate), adsorptive carriers (e.g., kaolin and bentonite), preservatives, sweeteners, coloring agents, flavoring agents (e.g., citric acid, menthol, glycine or orange powder), stabilizers (e.g., citric acid or sodium citrate), binders (e.g., hydroxypropylmethylcellulose), and mixtures thereof.
  • agents for retarding dissolution e.g., paraffin
  • resorption accelerators e.g., quaternary ammonium compounds
  • surface active agents e.g., cetyl alcohol, glycerol monostearate, and sodium lauryl sulfate
  • adsorptive carriers
  • the drug substance is not added to the high shear bowl first.
  • the typical blending time for the blending in the high shear granulator is from about 10 minutes to about 15 minutes. Although blending times greater than 15 minutes can be used, care should be taken not to demix the blend.
  • the granulator impeller speed is typically run at about 55% to about 65% unit capacity and the chopper is preferably run at the slowest speed setting. Excessive impeller speeds could lead to fluidization of the blend and produce a blend potency loss.
  • the active blend is blended in a twin shell "V” or bin blender.
  • the typical blending time is about 5 minutes, although small scale lots have been successfully blended up to about 15 minutes.
  • the lubricant is then added to the active blend and blended for about 5 minutes in the twin shell "V” or bin blender.
  • the process described above provides efficient mixing and a more uniform distribution of the active ingredient without significant degradation of the active ingredient; however, the loss of active ingredient due to adherence or attraction of the compound to the metal surfaces of the equipment (e.g., blades and vessel surfaces) presented an additional challenge especially for low dosage formulations (e.g., less than 4 mg per unit dose).
  • a glidant such as talc did not resolve the problem.
  • talc did not completely prevent adhesion to the metal surface.
  • silicon dioxide which is a submicron fumed silica prepared by the vapor-phase hydrolysis of a silicon compound, such as silicon tetrachloride.
  • Colloidal silica is an amorphous powder which is available commercially from a number of sources, including Cabot Corporation, Boston, MA (Cab-O-SilTM); Degussa, Inc., D ⁇ sseldorf, Germany (AerosilTM); E.I. DuPont & Co., Wilmington, DE; and W.R. Grace & Co., Columbia, MD (SyloidTM).
  • Colloidal silicon dioxide is also known as colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride, and silicon dioxide fumed, among others.
  • a variety of commercial grades of colloidal silicon dioxide are produced by varying the manufacturing process. These modifications do not affect the silica content, specific gravity, refractive index, color or amorphous form.
  • the mean particle size for the silicon dioxide is generally less than or equal to about 15 ⁇ m/bulk density (less than or equal to about 21.0 lbs./ft 3 (336 kg/m 3 )).
  • the silicon dioxide is in the form of a dry powder and not a liquid suspension.
  • the silicon dioxide is generally present in an amount from about 0.1 to about 2% by weight of the dosage form, preferably, in an amount from about 0.15 to about 1.0% by weight and most preferably in an amount from about 0.25 to about 0.75% by weight of the dosage form.
  • Suitable salt derivatives include halides, thiocyanates, sulfates, bisulfates, sulfites, bisulfites, arylsulfonates, alkylsulfates, phosphonates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphonates, alkanoates, cycloalkylalkanoates, arylalkonates, adipates, alginates, aspartates, benzoates, fumarates, glucoheptanoates, glycerophosphates, lactates, maleates, nicotinates, oxalates, palmitates, pectinates, picrates, pivalates, succinates, tartarates, citrates, camphorates, camphorsulfonates, digluconates, trifluoroacetates, and the like.
  • a preferred salt of compounds of Formula (I) is tartrate (in particular, D-tartrate) or citrate.
  • a preferred compound is lasofoxifene (c/s-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]- 5,6,7,8-tetrahydronaphthalen-2-ol).
  • the active ingredient is generally present in a pharmaceutical composition in an amount less than or equal to about 10% w/w.
  • the active ingredient is typically present in the pharmaceutical composition in an amount less than 4.0% w/w active ingredient, more preferably > about 0.01% w/w active ingredient and ⁇ 4% w/w active ingredient, even more preferably > about 0.01% w/w active ingredient and ⁇ about 3.5% w/w active ingredient, most preferably > about 0.1% w/w active ingredient and ⁇ about 2.5% w/w active ingredient).
  • the pharmaceutical composition can be used to produce unit dosage forms containing about 0.05 mg to about 10.0 mg active ingredient per unit dosage, preferably, about 0.1 mg to about 5.0 mg active ingredient per unit dosage.
  • the tablet size i.e., unit dosage form
  • the tablet size is typically between about 100 mg and 600 mg.
  • "low dosage form” refers to a unit dose containing less than about 5.0 mg active ingredient.
  • a typical low dosage form contains between about 0.01 and about 5.0 mg active ingredient, preferably between about 0.05 mg and about 4.0 mg, more preferably between about 0.1 mg and about 3.5 mg, most preferably between about 0.1 mg and 2.5 mg.
  • the tablet formulation for a 0.25 mg, 0.1 mg and 0.05 mg tablet typically consists of a blend containing about 0.14% w/w active ingredient and the tablet size is varied to achieve the proper dosage; whereas, a 0.5 mg tablet formulation generally contains a blend having about 0.68% w/w active ingredient.
  • the concentration of active ingredient in the final pharmaceutical composition is generally adjusted by increasing or decreasing the amount of diluent (e.g., lactose) added to the formulation.
  • the tablets are generally prepared by compression in a rotary press. However, the particular method used for tablet formation is non-limiting and is well known to those skilled in the art. After formation of the tablets, the tablets are often coated with one or more coatings.
  • the tablet may be coated with a coating to mask flavor, to act as a sealant and/or to act as a receptor for printing a logo or trademark on the tablet surface.
  • a common coating is a sugar coating (e.g., sucrose or sorbitol coating).
  • the tablet may be coated with a film-forming protecting agent(s) to modify the dissolution properties of the tablet.
  • the tablet may be coated with a film-forming coating that resists dissolution for a predictable period of time thus resulting in a delayed or prolonged release of the active ingredient.
  • Suitable film-forming protecting agents include celluloses (e.g., hydroxypropyl- methylcellulose, hydroxypropyl cellulose, methylcellulose), polyvinyl pyrrolidone, and ethyl acrylate-methyl methacrylate copolymers.
  • the coating formulations may also include additives such as solubilizing agents (e.g., triacetin), preservatives, sweeteners, flavoring agents, coloring agents and other known additives to provide an elegant presentation of the drug.
  • the compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation.
  • the active pharmaceutical blend may be filled into capsules.
  • the particular capsule or method used to fill the capsule are not limiting and are well known to those skilled in the pharmaceutical manufacturing arts.
  • the pharmaceutical composition may be packaged in a variety of ways.
  • an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form.
  • Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like.
  • the container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package.
  • the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions.
  • compositions containing the compounds of Formula (I) described herein are useful in the treatment or prevention of, inter alia, breast cancer, osteoporosis, obesity, cardiovascular disease, hypercholesterolemia, endometriosis and prostatic disease. Accordingly, the pharmaceutical formulations and processes described herein containing the compounds of Formula (I) may be used in the manufacture of a medicament for the therapeutic applications described above. A therapeutically effective amount of the manufactured medicament may be administered to a human in need of such treatment or prevention.
  • therapeutically effective amount refers to an amount of active ingredient which is capable of inhibiting or preventing the various pathological conditions or symptoms thereof and sequelae, referred to above.
  • the terms “inhibit” or “inhibiting” refers to prohibiting, treating, alleviating, ameliorating, halting, restraining, slowing or reversing the progression, or reducing the severity of a pathological condition or symptom related to or resultant from the respective condition being treated.
  • the pharmaceutical formulations may be used for both medical therapeutic (acute or chronic) and/or prophylactic (prevention) administration as appropriate.
  • the dose, frequency and duration will vary depending on such factors as the nature and severity of the condition being treated, the age and general health of the host and the tolerance of the host to the active ingredient.
  • the pharmaceutical composition or medicament may be given in a single daily dose or in multiple doses during the day. The regimen may last from about 2-3 days to several weeks or longer.
  • the composition is administered to a human patient once to four times a day with a unit dosage of about 0.05 mg to about 50 mg, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration.
  • a preferred dosing regimen for a human patient is a daily administration of about 0.25 mg per kg to about 25 mg per kg.
  • Lasofoxifene was prepared as described in U.S. Patent No. 5,552,412 and reproduced below.
  • the aqueous layer was further washed with Et 2 O (2x).
  • the combined organic layers were dried (MgSO ), filtered, and concentrated to provide 6-methoxy-1-tetralone (22 g).
  • the aqueous layer was basified to pH 12 with 5 N NaOH and 15% aqueous (NH ) 2 CO 3 (1000 mL) was added.
  • the aqueous mixture was extracted with CH 2 CI 2 (2x).
  • the organic solution was dried (MgSO ), filtered, and concentrated to provide a brown oil. Impurities were distilled off (110°- 140°C @0.2 mmHg) to yield the product (74 g, 57%).
  • the off-white solid was dissolved in CH 2 CI 2 and MeOH and was filtered away from the Celite. The organic solution was washed with 0.5 N aq HCI followed by saturated NaHCO 3 (aq). The organic solution was dried (MgSO 4 ), filtered, and concentrated to provide a brown solid (21.5 g, 83%).
  • the hydrobromide salt (9.6 g, 69%) was dissolved in CHCIs/MeOH and was stirred with saturated NaHCO 3 (aq). The layers were separated and the aqueous layer was further extracted with CHCIs/MeOH. The combined organic layers were dried (MgSO 4 ), filtered, and concentrated to yield product as an off-white foam.
  • Example 1 The following materials used in Example 1 may be obtained from the corresponding sources listed below: AvicelTM PH101 FMC Pharmaceutical (Philadelphia,
  • PA microcrystalline cellulose
  • Lactose Fast FloTM 316 Foremost Corp. Baraboo, Wl
  • magnesium stearate Mallinckrodt St. Louis, MO
  • sodium croscarmellose FMC Pharmaceutical Philadelphia,
  • Lasofoxifene Conventional Wet Granulation Process (Comparative process) The following ingredients were added to a high shear blender in the listed order. lactose 5.000 g microcrystalline cellulose 17.432 g sodium croscarmellose 1 .000 g hydroxypropyl cellulose 1 .250 g silicon dioxide 0.125 g
  • the mixture was blended for approximately 15 minutes. While blending, an appropriate amount of water (approximately 63% w/w of dry blend) was added over a 8.5 minute period and then allowed to continue blending for an additional 30 seconds to achieve the desired wet mass. The wet mass was then dried to a moisture level less than about 2% under vacuum (about 50 millibar (mB)). The dried granulation was milled through a conical mill fitted with a 0.04 inch (0.10 cm) screen and round edge impeller set at 1750 rpm speed. The mixture was blended for about 10 minutes in a 150 cc glass bottle on a Turbula mixer. Magnesium stearate (0.125 g) was added to the mixture and then blended for about 5 minutes. The active blend was then compressed into tablets using a KilianTM T100 tablet press (available from Kilian & Co., Inc., Horsham, PA).
  • KilianTM T100 tablet press available from Kilian & Co., Inc., Horsham, PA.
  • Lasofoxifene Drug In Solution Wet Granulation Process (Comparative process) Water (100 mL) was added to a 250 mL glass beaker equipped with a mixer. While stirring, ⁇ -cyclodextrin sulfobutyl ether (0.452 g) was added followed by the lasofoxifene (0.113 g) and allowed to stir until the ⁇ - cyclodextrin sulfobutyl ether and lasofoxifene dissolved and a solution was formed. The following ingredients were then added in the order listed into a high shear blender. lactose 5.000 g silicified microcrystalline cellulose 17.540 g sodium croscarmellose 1.000 g hydroxypropyl cellulose 1.250 g
  • the mixture was blended for about 2 minutes. While blending, the lasofoxifene:water solution was added over a 3 minute period. The wet mass was then dried to a moisture level of less than about 1% in a 50°C forced hot air oven. The dried granulation was passed through a conical mill fitted with a 0.055 inch (0.14 cm) screen and round edge impeller set at 1750 rpm speed. Magnesium stearate (0.125 g) was added to the mixture and then blended for about 5 minutes. The active blend was then compressed into tablets using a ManestyTM F-Press tablet press (available from Thomas Engineering Inc., Hoffman Estates, IL).
  • Lasofoxifene Dry Granulation Process The following ingredients were added in the order listed into a high shear blender lactose 1052.25 g microcrystalline cellulose 375.00 g croscarmellose sodium 45.00 g silicon dioxide 7.50 g Lasofoxifene 5.25 g
  • the lactose, microcrystalline cellulose, croscarmellose sodium and silicon dioxide were blended for 5 minutes.
  • the lasofoxifene was added next and blended for about 15 minutes.
  • the active blend was then discharged from the high shear blender and blended for about 5 minutes in a twin shell "V" blender.
  • Magnesium stearate (7.50 g) was added to the active blend and blended for about 5 minutes.
  • the active blend was roller compacted on a Vector FreundTM roller compactor unit and milled through a rotating granulator fitted with a 0.033" (0.084 cm) screen (both available from Vector Corp., Marion, IA).
  • the active granulation was blended for about 5 minutes in a twin shell "V” blender.
  • Another portion of magnesium stearate (7.50 g) was added to the granulation and blended for about 5 minutes.
  • the final blend was compressed into tablets on a KilianTM T100 rotary press.
  • Table 1 summarizes the stability results by high pressure liquid chromatography observed for the three different processes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Inorganic Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/IB2002/000766 2001-05-01 2002-03-13 Method for manufacturing a low dose pharmaceutical composition WO2002087546A2 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
DK02702671T DK1383482T3 (da) 2001-05-01 2002-03-13 Fremgangsmåde til fremstilling af en farmaceutisk lavdoseringssammensætning
DE60221238T DE60221238T2 (de) 2001-05-01 2002-03-13 Herstellungsverfahren für niedrig dosierte pharmazeutische zusammensetzung
AU2002236166A AU2002236166B2 (en) 2001-05-01 2002-03-13 Method for manufacturing a low dose pharmaceutical composition
MXPA03009391A MXPA03009391A (es) 2001-05-01 2002-03-13 METODO PARA FABRICAR UNA COMPOSICIoN FARMACEUTICA DE DOSIS BAJA.
NZ528886A NZ528886A (en) 2001-05-01 2002-03-13 A dry process for manufacturing a low dose pharmaceutical composition having uniform drug distribution and potency
JP2002584892A JP2004531537A (ja) 2001-05-01 2002-03-13 一様な薬剤分布と効力を有する低用量製薬組成物の製造方法
CA002445519A CA2445519C (en) 2001-05-01 2002-03-13 Method for manufacturing a low dose pharmaceutical composition
IL15839002A IL158390A0 (en) 2001-05-01 2002-03-13 Method for manufacturing a low dose pharmaceutical composition
BR0209283-2A BR0209283A (pt) 2001-05-01 2002-03-13 Método para a fabricação de uma composição farmacêutica de baixa dosagem tendo distribuição e potência de droga uniforme
KR1020037014223A KR100568380B1 (ko) 2001-05-01 2002-03-13 저 투약량 약학 조성물의 제조 방법
EP02702671A EP1383482B1 (en) 2001-05-01 2002-03-13 Method for manufacturing a low dose pharmaceutical composition
EEP200300537A EE200300537A (et) 2001-05-01 2002-03-13 Meetod madalaannuselise farmatseutilise kompositsiooni tootmiseks
EA200301040A EA005949B1 (ru) 2001-05-01 2002-03-13 Способ производства фармацевтической композиции низкой дозы
YUP-815/03A YU81503A (sh) 2001-05-01 2002-03-13 Postupak za proizvodnju farmaceutskog preparata sa niskom dozom, koji ima uniformnu raspodelu i snagu leka
APAP/P/2003/002900A AP2003002900A0 (en) 2001-05-01 2002-03-13 Method for manufacturing a low dose pharmaceutical composition
HU0401391A HUP0401391A3 (en) 2001-05-01 2002-03-13 Method for manufacturing a low dose pharmaceutical composition having uniform drug distribution and potency and the pharmaceutical compositin
UA2003109816A UA75135C2 (en) 2001-05-01 2002-03-13 Dry granulation method for manufacturing pharmaceutical composition containing tetrahydronaphthalene-2-ol derivative and low dosage tablet compositions
SK1355-2003A SK286536B6 (sk) 2001-05-01 2002-03-13 Spôsob granulácie za sucha na prípravu farmaceutickej kompozície
IS6985A IS6985A (is) 2001-05-01 2003-10-09 Aðferð til framleiðslu á lágskammta lyfjasamsetningu
NO20034709A NO20034709L (no) 2001-05-01 2003-10-21 Fremgangsmåte for fremstilling av lav dose farmasöytisk sammensetning med jevn medikament fordeling og potens
HR20030858A HRP20030858A2 (en) 2001-05-01 2003-10-21 Method for manufacturing a low dose pharmaceutical composition having uniform drug distribution and potency
HK04108533A HK1065705A1 (en) 2001-05-01 2004-10-30 Method for manufacturing a low dose pharmaceuticalcomposition having uniform drug distribution and potency

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US28784101P 2001-05-01 2001-05-01
US60/287,841 2001-05-01

Publications (2)

Publication Number Publication Date
WO2002087546A2 true WO2002087546A2 (en) 2002-11-07
WO2002087546A3 WO2002087546A3 (en) 2003-02-13

Family

ID=23104578

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2002/000766 WO2002087546A2 (en) 2001-05-01 2002-03-13 Method for manufacturing a low dose pharmaceutical composition

Country Status (44)

Country Link
US (2) US7037530B2 (sh)
EP (1) EP1383482B1 (sh)
JP (1) JP2004531537A (sh)
KR (1) KR100568380B1 (sh)
CN (1) CN1240375C (sh)
AP (1) AP2003002900A0 (sh)
AR (1) AR033288A1 (sh)
AT (1) ATE367152T1 (sh)
AU (1) AU2002236166B2 (sh)
BG (1) BG108297A (sh)
BR (1) BR0209283A (sh)
CA (1) CA2445519C (sh)
CZ (1) CZ20032959A3 (sh)
DE (1) DE60221238T2 (sh)
DK (1) DK1383482T3 (sh)
DO (1) DOP2002000389A (sh)
EA (1) EA005949B1 (sh)
EC (1) ECSP034826A (sh)
EE (1) EE200300537A (sh)
ES (1) ES2286226T3 (sh)
GE (1) GEP20053654B (sh)
GT (1) GT200200078A (sh)
HK (1) HK1065705A1 (sh)
HR (1) HRP20030858A2 (sh)
HU (1) HUP0401391A3 (sh)
IL (1) IL158390A0 (sh)
IS (1) IS6985A (sh)
MA (1) MA27017A1 (sh)
MX (1) MXPA03009391A (sh)
NO (1) NO20034709L (sh)
NZ (1) NZ528886A (sh)
OA (1) OA12596A (sh)
PA (1) PA8544401A1 (sh)
PE (1) PE20021137A1 (sh)
PL (1) PL366453A1 (sh)
PT (1) PT1383482E (sh)
SK (1) SK286536B6 (sh)
TN (1) TNSN03106A1 (sh)
TW (1) TWI264311B (sh)
UA (1) UA75135C2 (sh)
UY (1) UY27277A1 (sh)
WO (1) WO2002087546A2 (sh)
YU (1) YU81503A (sh)
ZA (1) ZA200307819B (sh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006895A1 (en) * 2002-07-10 2004-01-22 Pfizer Products Inc. Lasofoxifene tablet and its coating
US7799273B2 (en) 2004-05-06 2010-09-21 Smp Logic Systems Llc Manufacturing execution system for validation, quality and risk assessment and monitoring of pharmaceutical manufacturing processes
USRE43527E1 (en) 2004-05-06 2012-07-17 Smp Logic Systems Llc Methods, systems, and software program for validation and monitoring of pharmaceutical manufacturing processes
CN103830196A (zh) * 2014-03-14 2014-06-04 王志刚 一种酒石酸拉索昔芬分散片及其制备方法
US10039718B2 (en) 2008-05-02 2018-08-07 Gilead Sciences, Inc. Use of solid carrier particles to improve the processability of a pharmaceutical agent

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1487790B1 (en) 2002-03-28 2010-03-03 Pfizer Products Inc. Purified lasofoxifene and a method for purification of racemic lasofoxifene by recrystallization
CA2652657A1 (en) * 2006-05-17 2008-11-27 Wm. Wrigley Jr. Company Method of preparing a food product
US8951562B2 (en) * 2006-11-10 2015-02-10 Atacama Labs Oy Method and apparatus or dry granulation
FI20080351A0 (fi) * 2008-05-09 2008-05-09 Atacama Labs Oy Prosessi matalan lääkepitoisuuden tabletin valmistamiseksi
FI20070521L (fi) 2006-11-10 2008-05-11 Atacama Labs Oy Rakeita, tabletteja ja rakeistusmenetelmä
CA2671727C (en) * 2006-12-20 2016-02-16 Genpharm Ulc A composition containing a bisphosphonic acid in combination with vitamin d
US20080181972A1 (en) * 2007-01-29 2008-07-31 Valentina Amico Compositions and Methods for Maintaining, Strengthening, Improving, or Promoting Eye Health
LT2487166T (lt) 2007-02-23 2016-11-10 Gilead Sciences, Inc. Terapinių agentų farmakokinetinių savybių moduliatoriai
CA2723409C (en) * 2008-05-09 2016-11-08 Atacama Labs Oy Method and apparatus for dry granulation
US20170065529A1 (en) 2015-09-09 2017-03-09 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
RS57142B1 (sr) 2008-06-06 2018-07-31 Boehringer Ingelheim Int Farmaceutski dozni oblik u vidu kapsule koji sadrži formulaciju suspenzije indolinon derivata
WO2010094535A1 (en) * 2009-01-29 2010-08-26 Ucb Pharma, S.A. Pharmaceutical compositions comprising 2-oxo-1-pyrrolidine derivatives
ES2520990T3 (es) * 2009-01-29 2014-11-12 Ucb Pharma, S.A. Composiciones farmacéuticas que comprenden derivados de 2-oxo-1-pirrolidina
US20140350945A1 (en) * 2013-05-22 2014-11-27 Professional Compounding Centers Of America System and Method for Validation of Pharmaceutical Composition Formulations
CN106176649B (zh) * 2016-08-31 2020-04-17 北京斯利安药业有限公司 叶酸vb12片及其制备方法
BR112019015904A2 (pt) * 2017-02-17 2020-03-24 Massachusetts Institute Of Technology Sistemas e métodos para a fabricação de comprimidos, incluindo comprimidos farmacêuticos
CZ309820B6 (cs) * 2021-04-23 2023-11-08 Pro.Med.Cs Praha A.S. Způsob přípravy pevné lékové formy obsahující kompozici s nízkým obsahem účinné látky

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1570993A (en) * 1976-05-21 1980-07-09 Fisons Ltd Pharmaceutical tablet formulation
EP0503521A1 (en) * 1991-03-12 1992-09-16 Akzo Nobel N.V. Low dose dry pharmaceutical preparations
EP0700680A1 (en) * 1994-09-06 1996-03-13 Bristol-Myers Squibb Company Gepirone dosage form
US5552412A (en) * 1995-01-09 1996-09-03 Pfizer Inc 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen2-ol compounds which are useful for treating osteoporosis
WO1997016434A1 (en) * 1995-11-02 1997-05-09 Pfizer Inc. (-) cis-6(s)-phenyl-5(r)[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol d-tartrate
WO2001015724A1 (en) * 1999-08-31 2001-03-08 Mutual Pharmaceutical Company, Inc. Improved stable formulations of ace inhibitors, and methods for preparation thereof

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725555A (en) * 1967-08-01 1973-04-03 Ciba Geigy Corp Bactericidal compositions and method of killing bacteria using bis-(phenoxyphenyl) carbonates
US3725556A (en) * 1970-11-12 1973-04-03 D Hanssen Method of manufacturing rapidly disintegrating pharmaceutical tablets
US4013785A (en) * 1975-03-21 1977-03-22 Bristol-Myers Company Apap tablet containing fumed silica and process for manufacturing same
DE2845326C2 (de) * 1978-10-18 1985-05-23 Beiersdorf Ag, 2000 Hamburg Verwendung einer spezifischen mikrodispersen, amorphen, porösen Kieselsäure zur Herstellung von Digoxin enthaltenden Tabletten mit stark beschleunigter Wirkstoff-Freisetzung
US4489026A (en) * 1982-09-07 1984-12-18 The Upjohn Company Process for preparing solid unit dosage forms of ultra-low dose drugs
US5004613A (en) * 1987-07-27 1991-04-02 Mcneil-Ppc, Inc. Oral sustained release pharmaceutical formulation and process
US5047246A (en) * 1988-09-09 1991-09-10 Bristol-Myers Company Direct compression cyclophosphamide tablet
US5107331A (en) * 1989-03-07 1992-04-21 The Color Group Method and apparatus for producing half-tone separations at the same screen angle
US5376645A (en) * 1990-01-23 1994-12-27 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
KR0166088B1 (ko) * 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
US5464632C1 (en) * 1991-07-22 2001-02-20 Prographarm Lab Rapidly disintegratable multiparticular tablet
US5358941A (en) * 1992-12-02 1994-10-25 Merck & Co., Inc. Dry mix formulation for bisphosphonic acids with lactose
US5928668A (en) * 1993-12-21 1999-07-27 Applied Analytical Industries, Inc. Method for dry blend compression of medicaments
US5976570A (en) * 1993-12-21 1999-11-02 Applied Analytical Industries, Inc. Method for preparing low dose pharmaceutical products
ES2082723B1 (es) * 1994-07-20 1996-10-01 Lilly Sa Formulacion farmaceutica de fluoxetina en forma dispersable.
ES2079327B1 (es) * 1994-12-13 1996-08-01 Lilly Sa Formulaciones farmaceuticas de cefaclor.
GB9501127D0 (en) * 1995-01-20 1995-03-08 Wellcome Found Tablet
US5726168A (en) * 1995-10-12 1998-03-10 Eli Lilly And Company Lipophilic benzothiophenes
US5733578A (en) * 1995-11-15 1998-03-31 Edward Mendell Co., Inc. Directly compressible high load acetaminophen formulations
IL120266A (en) * 1996-02-28 2005-05-17 Pfizer Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions
US5916916A (en) * 1996-10-10 1999-06-29 Eli Lilly And Company 1-aryloxy-2-arylnaphthyl compounds, intermediates, compositions, and methods
JPH10204082A (ja) * 1996-10-25 1998-08-04 Eli Lilly & Co 選択的エストロゲンレセプターモジュレーターとしての活性を有する置換されたベンゾ［ｂ］チオフェン化合物
US6080427A (en) * 1997-04-17 2000-06-27 Bristol-Myers Squibb Company Cefadroxil monohydrate tablet formulation
PT889056E (pt) * 1997-07-01 2006-07-31 Pfizer Prod Inc Processo para produzir um,a ciclodextrina.
US6300367B1 (en) * 1999-04-20 2001-10-09 Protein Technologies International, Inc. Composition for and method of preventing or treating breast cancer
AR029538A1 (es) * 2000-07-06 2003-07-02 Wyeth Corp Composiciones farmaceuticas de agentes estrogenicos

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1570993A (en) * 1976-05-21 1980-07-09 Fisons Ltd Pharmaceutical tablet formulation
EP0503521A1 (en) * 1991-03-12 1992-09-16 Akzo Nobel N.V. Low dose dry pharmaceutical preparations
EP0700680A1 (en) * 1994-09-06 1996-03-13 Bristol-Myers Squibb Company Gepirone dosage form
US5552412A (en) * 1995-01-09 1996-09-03 Pfizer Inc 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen2-ol compounds which are useful for treating osteoporosis
WO1997016434A1 (en) * 1995-11-02 1997-05-09 Pfizer Inc. (-) cis-6(s)-phenyl-5(r)[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol d-tartrate
WO2001015724A1 (en) * 1999-08-31 2001-03-08 Mutual Pharmaceutical Company, Inc. Improved stable formulations of ace inhibitors, and methods for preparation thereof

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006895A1 (en) * 2002-07-10 2004-01-22 Pfizer Products Inc. Lasofoxifene tablet and its coating
US7799273B2 (en) 2004-05-06 2010-09-21 Smp Logic Systems Llc Manufacturing execution system for validation, quality and risk assessment and monitoring of pharmaceutical manufacturing processes
USRE43527E1 (en) 2004-05-06 2012-07-17 Smp Logic Systems Llc Methods, systems, and software program for validation and monitoring of pharmaceutical manufacturing processes
US8491839B2 (en) 2004-05-06 2013-07-23 SMP Logic Systems, LLC Manufacturing execution systems (MES)
US8591811B2 (en) 2004-05-06 2013-11-26 Smp Logic Systems Llc Monitoring acceptance criteria of pharmaceutical manufacturing processes
US8660680B2 (en) 2004-05-06 2014-02-25 SMR Logic Systems LLC Methods of monitoring acceptance criteria of pharmaceutical manufacturing processes
US9008815B2 (en) 2004-05-06 2015-04-14 Smp Logic Systems Apparatus for monitoring pharmaceutical manufacturing processes
US9092028B2 (en) 2004-05-06 2015-07-28 Smp Logic Systems Llc Monitoring tablet press systems and powder blending systems in pharmaceutical manufacturing
US9195228B2 (en) 2004-05-06 2015-11-24 Smp Logic Systems Monitoring pharmaceutical manufacturing processes
US9304509B2 (en) 2004-05-06 2016-04-05 Smp Logic Systems Llc Monitoring liquid mixing systems and water based systems in pharmaceutical manufacturing
US10039718B2 (en) 2008-05-02 2018-08-07 Gilead Sciences, Inc. Use of solid carrier particles to improve the processability of a pharmaceutical agent
CN103830196A (zh) * 2014-03-14 2014-06-04 王志刚 一种酒石酸拉索昔芬分散片及其制备方法

Also Published As

Publication number Publication date
AR033288A1 (es) 2003-12-10
US20060093667A1 (en) 2006-05-04
ECSP034826A (es) 2004-02-26
HUP0401391A2 (hu) 2004-12-28
GT200200078A (es) 2003-01-31
YU81503A (sh) 2006-08-17
HUP0401391A3 (en) 2009-06-29
WO2002087546A3 (en) 2003-02-13
SK13552003A3 (sk) 2004-09-08
US7037530B2 (en) 2006-05-02
NO20034709L (no) 2003-10-31
DE60221238D1 (de) 2007-08-30
KR20040015226A (ko) 2004-02-18
AP2003002900A0 (en) 2003-12-31
TNSN03106A1 (fr) 2005-12-23
ATE367152T1 (de) 2007-08-15
US20030004182A1 (en) 2003-01-02
KR100568380B1 (ko) 2006-04-05
EA005949B1 (ru) 2005-08-25
ZA200307819B (en) 2004-10-07
JP2004531537A (ja) 2004-10-14
ES2286226T3 (es) 2007-12-01
GEP20053654B (en) 2005-11-10
DOP2002000389A (es) 2002-11-30
IS6985A (is) 2003-10-09
EA200301040A1 (ru) 2004-04-29
CA2445519A1 (en) 2002-11-07
EP1383482A2 (en) 2004-01-28
DK1383482T3 (da) 2007-10-29
PA8544401A1 (es) 2003-07-28
SK286536B6 (sk) 2008-12-05
OA12596A (en) 2006-06-08
CZ20032959A3 (cs) 2004-01-14
HK1065705A1 (en) 2005-03-04
MA27017A1 (fr) 2004-12-20
BR0209283A (pt) 2004-07-13
EP1383482B1 (en) 2007-07-18
MXPA03009391A (es) 2004-01-29
PE20021137A1 (es) 2002-12-14
EE200300537A (et) 2004-04-15
US7176221B2 (en) 2007-02-13
PT1383482E (pt) 2007-09-20
CN1531423A (zh) 2004-09-22
NO20034709D0 (no) 2003-10-21
PL366453A1 (en) 2005-02-07
CA2445519C (en) 2009-01-20
DE60221238T2 (de) 2007-10-31
UY27277A1 (es) 2002-11-29
TWI264311B (en) 2006-10-21
BG108297A (bg) 2005-07-29
AU2002236166B2 (en) 2006-12-07
HRP20030858A2 (en) 2005-08-31
NZ528886A (en) 2005-04-29
CN1240375C (zh) 2006-02-08
IL158390A0 (en) 2004-05-12
UA75135C2 (en) 2006-03-15

Similar Documents

Publication Publication Date Title
US7176221B2 (en) Low dose pharmaceutical composition having uniform drug distribution and potency
US7553500B2 (en) Pharmaceutical composition having uniform drug distribution and potency
AU2002236166A1 (en) Method for manufacturing a low dose pharmaceutical composition
JP3909998B2 (ja) 経口投与製剤

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 1200300971

Country of ref document: VN

Ref document number: P-815/03

Country of ref document: YU

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 2003/07819

Country of ref document: ZA

Ref document number: 200307819

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 955/MUMNP/2003

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/009391

Country of ref document: MX

Ref document number: 158390

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 528886

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2002702671

Country of ref document: EP

Ref document number: P20030858A

Country of ref document: HR

Ref document number: 200301040

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 2002236166

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2445519

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 10829702

Country of ref document: BG

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1-2003-501083

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: AP/P/2003/002900

Country of ref document: AP

Ref document number: PV2003-2959

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 13552003

Country of ref document: SK

Ref document number: 5339

Country of ref document: GE

Ref document number: 028092554

Country of ref document: CN

Ref document number: 2002584892

Country of ref document: JP

Ref document number: 1020037014223

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV2003-2959

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 2002702671

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 528886

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 528886

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 2002702671

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: PV2007-829

Country of ref document: CZ

ENP Entry into the national phase

Ref document number: 1512007

Country of ref document: SK

Kind code of ref document: A